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Taking a Precision Cancer Medicine Approach to Develop Oncology Drugs That Target Mitosis

2Copyright © 2018 Trovagene, Inc.

Forward-Looking Statements

Certain statements in this presentation are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of words such as "anticipate," "believe," "forecast," "estimated" and "intend" or other similar terms or expressions that concern Trovagene's expectations, strategy, plans or intentions.

These forward-looking statements are based on Trovagene's current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. While the list of factors presented in the 10-K is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Forward-looking statements included herein are made as of the date hereof, and Trovagene does not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances.


Trovagene’s Management TeamProven Leadership in Oncology

Tom Adams, PhDExecutive Chairman

Mark Erlander, PhDChief Scientific Officer

George Samuel, Esq.VP, General Counsel

Vicki KelemenVP, Clinical Development

Sandra Silberman, MD, PhDChief Medical Advisor


Scientific AdvisorsPrincipal Investigators and Collaborators

► Jorge Cortes, MD – MD Anderson– Deputy Chair, Professor of Medicine, Department of

Leukemia and Director of CML and AML programs

► Amer Zeidan, MBBS, MHS – Yale – Assistant Professor of Medicine

► Glenn Bubley, MD – Beth Israel Deaconess Medical Center– Director, Multidisciplinary Genitourinary Cancer Program

► David Einstein, MD – Beth Israel Deaconess Medical Center– Principal Investigator, mCRPC Phase 2 Trial

► Filip Janku, MD, PhD – MD Anderson– Associate Professor, Investigational Cancer Therapeutics

(Phase 1 Clinical Trials Program)

► Michael Yaffe, MD, PhD – MIT– Director, MIT Center for Precision Cancer Medicine,

Professor of Biology and Biological Engineering

► Heinz-Josef Lenz, MD, FACP – Norris Comprehensive Cancer Center, USC– Associate Director Adult Oncology and Co-Leader

Gastrointestinal Cancers


Strategy for Oncology Drug Development

►Taking a precision cancer medicine approach to develop Onvansertib, a first-in-class, 3rd generation PLK1 inhibitor

►Leveraging a proven cancer target, PLK1

►Incorporating predictive clinical biomarkers

►Combining Onvansertib with already approved drugs– Phase 1b/2 trial of Onvansertib + cytarabine or decitabine in Acute

Myeloid Leukemia (AML)

– Phase 2 trial of Onvansertib + abiraterone acetate (Zytiga®)/prednisone in metastatic Castration-Resistant Prostate Cancer (mCRPC)

– Phase 1b/2 trial of Onvansertib + FOLFIRI and bevacizumab in metastatic Colorectal Cancer (mCRC)


Onvansertib – Pipeline Within a MoleculeOpportunities in Leukemias/Lymphomas and Solid Tumors

Preclinical Phase 1 Phase 2

Solid Tumor Cancers

Leukemias & Lymphomas

Metastatic Castration-Resistant ProstatePhase 2 trial in combination with Zytiga® (abiraterone acetate)/prednisone

Lung

Colorectal (CRC)

Ovarian

Others (adrenocortical, sarcomas, head and neck, skin, liver, pancreatic, ampullary)

Triple Negative Breast

Acute Myeloid Leukemia – Orphan Drug Designation in the U.S. and EuropePhase 1b/2 trial in combination with low-dose cytarabine (LDAC) or decitabine


Licensed Drug Candidate from NMSOnvansertib – Polo-like Kinase 1 (PLK1) Inhibitor

► Largest oncology research and development company in Italy

► Developed anthracycline class of drugs (doxorubicin)

► Leader in protein kinase drug development (Polo-like Kinase Inhibitors)

► Identification and validation of molecular targets focused on driver oncogenes

► Excellent track record licensing innovative drugs to pharma/biotech companies including: Genentech (Roche), Ignyta (Roche), Novartis

Oncology Drug Discovery

Developing Oncology Drugs That Target Mitosis

IND = Investigational New Drug

► Licensed global development and commercialization rights for Onvansertib

► Nerviano will continue manufacturing GMP API and finished drug

► Two active INDs in place with the FDA

► Financing in place to advance clinical programs into mid-2019


Nerviano Oncology Portfolio Success

Licensed Preclinical Phase 1 Phase 2 Phase 3 Registered

Encorafenib (B-RAF IP) Melanoma Braf mutation in combination with binimetinib

Entrectinib (TRK, ROS, ALK) Non-Small Cell Lung

Milciclib (CDK, other kinases) Thymic Cancer

MPS1 Inhibitor Solid Tumors

Onvansertib (PLK1 inhibitor) AML and mCRPC

ADC (PNU-652)

ADC (NMS-P945)

► Excellent track record licensing innovative drugs to pharma/biotech companies that have subsequently received FDA breakthrough status and priority review designation

Leveraging a Proven Cancer Target


PLK1 – Established Target for Cancer Therapy

► Polo-like Kinase 1 (PLK1)– Belongs to a family of kinases

(PLK1,2,3,4,5)

– Dysfunction leads to cancer formation and progression

– Over-expressed in dividing cancer cells

– Inhibition leads to cancer cell death

PLK1 Plays a Critical Role in Initiation, Maintenance and Completion of Mitosis

1Liu et al- PLK1, A Potential Target for Cancer Therapy; Translational Oncology – Vol. 10 – pp. 22-32; February 2017

Cell-cycle arrest


PLK1 – Over-Expressed in Multiple Cancers

Over-Expression of PLK1 Observed in Numerous Cancers1

Tumor Type PLK1 Fold Change Over-ExpressionAML 13.0

B-cell Lymphoma 56.3

Prostate 3.3

Adrenocortical 4.5

Lung Adeno 9.7

Lung Squamous 20.8

Breast 11.3

Esophageal 10.2

Stomach 4.8

Colon 2.5

Head & Neck 4.2

Pancreatic 2.2

Ovarian 31.7

Glioblastoma 12.4

Kidney 4.7

Liver 11.7

Uterine 21.3

Bladder 9.11Liu et al- PLK1, A Potential Target for Cancer Therapy; Translational Oncology – Vol. 10 – pp. 22-32; February 2017

Publications

Developing OnvansertibFirst-in-Class 3rd Generation PLK1


Onvansertib First-in-Class 3rd Generation PLK1Best-in-Class Attributes


Onvansertib Intellectual Property

► Four worldwide patent families

– Genus, Compound, Combinations, Salt

► Mature portfolio– Granted in most major

jurisdictions

► Patent term 2030 plus up to 5 years extension


Onvansertib – Highly-Selective Only for PLK1

► Tested against >260 kinases

► PLK1 was the only active target (IC50 of 2nM)

1Data on File, Trovagene, Inc.

Selective PLK1 Inhibitor

Causes cancer cell death by G2M arrest AML-NS8 Patient-Derived Cells Treated with

200 nM Onvansertib for 24 Hrs1

PCM-075DMSO PCM-075 Control► Onvansertib blocks cell division (mitosis)

PLK MemberOnvansertib

IC50* (μM)

PLK1 0.002

PLK2 > 10

PLK3 > 10


Onvansertib Phase 1 Safety Trial1Favorable First-in-Human Data

Trial Design Trial Results

Solid Tumors: colorectal, pancreatic, lung, sarcomas, hepatocellular,

ampullary, prostate, ovarian, skin

1. Established safety and identified Phase 2 dose of 24 mg/m2/day

2. 16 patients evaluable with 30% stable disease

3. Only mild to moderate side effects

4. No GI disorders, mucositis, or hair loss

Phase 1 Dose Escalation Trial in Patients with Advanced or Metastatic Solid Tumors

Open-label dose escalation to assess safety and identify Phase 2 dose

19 patients administered Onvansertib orally, once daily for 5 consecutive

days, every 21-days

1Weiss G et al., Phase I dose escalation study of NMS-1286937, an orally available Polo-like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors – Invest. New Drugs DOI 10.1007/s10637-017-0491-7

Benefiting From Drug Class Experience


Drawbacks Associated with 1st and 2nd

Generation PLK Inhibitors

► Prior PLK inhibitors in development demonstrated significant clinical activity in

combination with standard-of-care chemotherapy in AML

► Major drawbacks, unrelated to efficacy of the drug class, resulted in discontinuation

of development

Non-Selective panPLK inhibitors targeting both normal and tumor cells

Serious adverse effects that are non-mechanism based

Intravenous formulation; relatively long half-life

Fixed dose; no option to increase time between treatment

Significant Toxicities

Sub-Optimal PK

No Dosing/Schedule Flexibility

No mandated anti-infective prophylaxisLethal Infections

Inability to identify patients most likely to respondNo Biomarker Strategy


Onvansertib – First-in-Class, 3rd Generation PLK1 Addresses Drawbacks of 1st and 2nd Generation

► Onvansertib product profile and clinical development program effectively addresses drawbacks associated with 1st and 2nd generation PLK inhibitors

Highly-Selective

Safe and Well Tolerated

Dosing and Treatment Schedule Flexibility

Only mild to moderate side effects reported

Selective only for PLK1 which is overexpressed in tumor cells

Orally administered and relatively short half-life of ~24 hours

Dose individualized to patients based on weight and body surface area; flexibility to increase time between treatment

Protocol mandated prophylactic anti-infectives for all patients

Ability to identify patients most likely to respond to therapy

Ideal PK Properties

Proactive Infection Management

Biomarker Strategy

Combination Therapy Approach


Onvansertib Combination Therapy Strategy

► Cornerstone of precision cancer medicine

► Onvansertib has demonstrated synergy with chemotherapies and targeted therapeutics

► Enhances efficacy (targets key pathways by synergy or additive effect)

► Reduces drug resistance, while providing therapeutic benefits1Mokhtari, R et al - Combination Therapy in Combatting Cancer – Oncotarget, 2017, Vol. 8 (No. 23), pp: 38022-38043


Onvansertib – Synergistic in Combination

► High PLK1 expression is associated with the most aggressive cancers

► Synergistic activity may enhance efficacy of standard-of-care therapies

1Alphabetical order. 2Preclinical data on file with PCM-075 and these combined therapeutics

Potentially Synergistic Drugs1,2

Abiraterone acetate

Bevacizumab

Bortezomib

Cisplatin

Cytarabine

Doxorubicin

FLT3 Inhibitors (Quizartinib)

Gemcitabine

HDAC Inhibitors (Belinostat)

Paclitaxel

Associated Cancers2

Leukemias/Lymphomas:

• Acute Myeloid Leukemia• Acute Lymphocytic Leukemia• Non-Hodgkin Leukemia• Multiple Myeloma

Solid Tumor Cancers:

• Castration-Resistant Prostate• Adrenocortical Carcinoma• Triple Negative Breast• Sarcomas• Small Cell Lung• Colon


Onvansertib Rationale for Combination with DNA Damaging Agents1,2

Active P

LK1

PLK1 Inhibited

1van Vugt & Yaffe, Cell Cycle 2010 9:2097-2101; 2van Vugt et al., 2010, PLoS 8:1-19

DNA Damaging Agents

• Cytarabine

• Doxorubicin

• Cisplatin

DNA Damage Response

(DDR) arrests cells at

G2/M checkpoint

G2/M

Arrest

Mitosis

1. Checkpoint adaptation

2. PLK1 inhibits DDR,

induces mitotic entry for

tumor cells & cell division

Cell Death

1. Keeps tumor cells in

G2/M arrest leading to

apoptosis

2. For cells that escape,

mitosis is blocked, also

leading to apoptosis


Onvansertib (PCM-075) + FLT3 InhibitorAcute Myeloid Leukemia (AML)

► 30% of AML patients have a FLT3 mutation1

► Quizartinib in Phase 3 clinical development2

► Combination of PCM-075 + quizartinib demonstrated:– 97% tumor growth inhibition

– Regression in FLT3 AML xenograft model3

1Kindler et al, Blood 2010; 116:5089-10. 2Stone et al, N Engl J Med 2017; 377:454-64. 3Data on File at Trovagene, Inc.

Evaluation of Efficacy of PCM-075 for MV-4-11 Human Acute Myeloid Leukemia (AML) Xenograft Model in NOD.SCID Mice

Treatment 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21VehiclePCM-075QuizartinibCombo

DosingSchedule


Onvansertib (PCM-075) + AbirateroneMetastatic Castration-Resistant Prostate Cancer

► PCM-075 + abiraterone demonstrated synergy1

► Combination enhances PCM-075 mechanism of action1

► Medical need to increase duration of response to anti-androgen drugs

1Yaffe, Michael, MD and Trovagene, 2017

C4-2 Castration-Resistant Prostate Cancer CellsIncreased Sensitivity to Abiraterone in the

Presence of PCM-075

*Expected = the calculated value of the effect of the addition of each drug as calculated by Michael Yaffe, MD - MIT

*PCM-075 PCM-075 + Abiraterone (expected*)PCM-075 + Abiraterone Synergy

Onvansertib (PCM-075) Clinical Development

Phase 1b/2 Acute Myeloid Leukemia (AML)

Phase 2 metastatic Castration-Resistant Prostate Cancer (mCRPC)

Phase 2 metastatic Colorectal Cancer (mCRC)


Clinical Development Roadmap

Acute Myeloid Leukemia

Prostate Cancer

Colorectal Cancer


Acute Myeloid Leukemia1

Significant Need for New Treatment Options

► Aggressive hematologic malignancy of immature blood cells

► 20,000 new cases, 10,400 deaths annually, and 5 year survival rate of 25%

► Treatment options vary based on patient condition / age, but can include: – Chemotherapy / Radiation / Stem Cell Transplant

► Preclinical in-vitro and in-vivo data demonstrate efficacy of Onvansertib* as single agent and in combination with drugs used to treat AML

*Orphan Drug Designation granted for Onvansertib by the FDA September, 2017 and by the EMA in July, 2018 ;1National Cancer Institute SEER 2016; 2Valsasina et al., Mol Cancer Ther; 11(4) April 2012

Acute Myeloid Leukemia


AML Clinical Development Landscape1

Medical Need for New Therapeutic Options

Company Market Cap Drug Combination Development

$15M Onvansertib (PLK1 inhibitor) Cytarabine / Decitabine Phase 1b/2

$104M Tosedosat (aminopeptidase activity inhibitor)

Cytrabine / 5-Azacytadine Phase 1/2

$288M Ficlatuzumab (antibody targeting HGF) Cytarabine Phase 1

$4.5BTibsovo (IDH1Inhibitor)

AG-221 (IDH2 Inhibitor)

Single Agent

Single Agent

FDA Approved

Phase 1/2

► The majority of therapeutic advances for AML have not come from the introduction of novel therapeutics but instead from optimizing use of older drugs2

► With increased understanding of the molecular pathogenesis of AML in recent years there is a significant opportunity to introduce new targeted therapeutics2

1www.clinicaltrials.gov; 2www.hematology.org/Thehematologist/Years-Best/8155.aspx

Significant Opportunity for New Therapeutic Options

http://www.clinicaltrials.gov/


► in-vitro studies1

– High sensitivity of hematological tumor cell lines to PCM-075

► in-vitro and in-vivo mode of action (MoA) studies2

– Xenograft model demonstrates dose dependent inhibition of PLK1 activity and G2/M arrest

► in-vivo efficacy in AML xenograft models2

– Dose dependent efficacy of PCM-075 in

• HL60 promyelocytic leukemia xenograft

• Disseminated AML patient derived xenografts (AML-PS)

– Combination of PCM-075 + cytarabine has greater survival than either agent alone (AML-PS)

Onvansertib (PCM-075) Scientific RationaleClinical Development in AML

1Source: Report No. N-0018670 Antiproliferative activity of NMS-1286937 in a panel of cell lines;2Valsasina et al., Mol Cancer Ther; 11(4) April 2012; 3ClinicalTrials.gov, NCT03303339: PCM-075 in Combination With Either Low-dose Cytarabine or Decitabine in Adult Patients With Acute Myeloid Leukemia (AML) - Data-on-file, Trovagene 2018


Orphan Drug Designation (ODD) in AML

In the U.S. and Europe

Regulatory and Financial Incentives

Extended Market Exclusivity


Onvansertib Comparative and Combination with Cytarabine in AML Models1,2

1Casolaro et al. (2013) PLOS One 8(3); 2Valsasina et al. (2012), Mol Cancer Ther 11(4)

*p = 0.001

VehiclePCM-075 60 mg/kg BIDCytarabine 75 mg/kg

Vehicle

PCM-075 60 mg/kg BID

Cytarabine 75 mg/kg

VehiclePCM-075 60 mg/kg BIDCytarabine 75 mg/kg

Vehicle

Onvansertib 60 mg/kg BID

Cytarabine 75 mg/kg

► Onvansertib + cytarabine in combination showed increased survival compared to either agent alone

In Vivo Disseminated Leukemia Models

– Onvansertib 120 mg/kg for 2 days repeated for 4 cycles with a 10-day rest

– Cytarabine IP at 75mg/kg for 5 cycles of 5 consecutive days with 7-day rest

– The combination was given at the same schedule, doses, and routes of the single agents

– Onvansertib 60 mg/kg BID (Days 1-2 with 5-day rest) + cytarabine 75 mg/kg IP Injection (Days 1-5 with 5-day rest)

– Onvansertib 120 mg/kg for 2 days repeated for 4 cycles with a 10-day rest

Vehicle

Onvansertib

Cytarabine

Combination

Surv

ival

%

AML-PS Combination

Time (Days)


Onvansertib Positioning in AMLPatient Selection Algorithm

AML Diagnosis 18,3761

cases/year

Eligible for Induction Treatment~11,000

Relapsed

& Refractory

30-50% 3,300 to

5,500

Onvansertib in combination with standard-of care chemotherapy and/or targeted therapeutics2

Responders 50-70%

Ineligible for

Induction Treatment

~7,400

Consolidation Treatment

1Visser et al. (2012), Eur J Cancer (48). Estimated cases in EU27 per year; 2e.g. Midostaurin for FLT3 mutation


Ongoing Phase 1b/2 Clinical Trial in AML

Phase 1b: Dose escalation to assess safety and identify recommended Phase 2 dose

► Administered orally, once daily on days 1-5 of each cycle (21-28 days)

12 mg/m2

18 mg/m2

27 mg/m2

40 mg/m2

Phase 2: Assess safety and preliminary antitumor activity

► Efficacy Endpoints: Rate of complete response (CR + CRi) defined as morphologic leukemia-free state (MLF)

► Exploratory Endpoints: Evaluation of pharmacodynamic and correlative biomarkers

Onvansertib in Combination with Either Low-Dose Cytarabine or Decitabine in Patients with Acute Myeloid Leukemia (AML)


Biomarker Strategy in AML

► Biomarkers will be measured and correlated with pharmacokinetic drug levels to assess: – Treatment effects by measuring % blast cells in blood and bone marrow– Inhibition of PLK1 by Onvansertib (Target Engagement) – Correlating underlying tumor genetics with treatment response

Genomic Profiling: Tumor Mutations

Immuno-ProfilingCell Isolation

DNA Isolation

Flow Cytometry

Cell IsolationProtein ExtractionPLK1 Target Engagement pTCTP/TCTP


Immuno-Profiling: Monitoring Leukemic Blast Cells in Response to Treatment

0

2 0

4 0

6 0

8 0

1 0 0

D a y s o f c y c le

% o

f le

uk

oc

yte

s

0 1 -0 0 2

0 7 -0 0 4

0 7 -0 1 0

1 5 8 15 22 1 5 8 15 22

C y c le 1 C y c le 2

% of Leukemic Cells in Blood

Onvansertib + LDACOnvansertib + Decitabine

0 1 -0 0 2 0 7 -0 0 4 0 7 -0 1 0 0 7 -0 0 9 0 7 -0 1 1 0 7 -0 1 30

5 0

1 0 0

% o

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uk

oc

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s

S c re e n in g

C y c le 1

C y c le 2

C y c le 4

L D A C D e c ita b in e

%Leukemic Cells in Bone Marrow(Trovagene analysis)

LDAC Decitabine

0

2 5

5 0

7 5

1 0 0


% o

f le

uk

oc

yte

s

0 7 -0 0 9

0 7 -0 1 1


0 7 -0 1 3


1 5 15 22 1 5 15 22 1 5 15 22 1 5 15 22 1 5 15 22

C y c le 5

%Leukemic Cells in Bone Marrow(Clinical site analysis)

0 1 -0 0 2 0 7 -0 1 0 0 7 -0 0 9 0 7 -0 1 30

2 0

4 0

6 0

8 0

1 0 0

% o

f le

uk

oc

yte

s

S c re e n in g

C y c le 1

C y c le 2

C y c le 4

C y c le 5

LDAC Decitabine1NCT03303339, ClinicalTrials.gov; “Onvansertib in Combination With Either Low-dose Cytarabine or Decitabine in Adult Patients With Acute Myeloid Leukemia (AML)


Target Engagement:

Monitoring PLK1 Inhibition Upon Treatment

TCTP

PLK1

TCTP

P

No Onvansertib

P

Onvansertib

PLK1

TCTP

TCTP

Onvansertib

P

► Onvansertib inhibits PLK1 kinase activity resulting in reduction in PLK1 substrates

phosphorylation; Translational Control Tumor Protein (TCTP) is phosphorylated by

PLK1

► PLK1 inhibition was assessed 3-hours following administration of Onvansertib at

peak concentration (Cmax)

1Cusshi U. et al, Phosphorylation of TCTP as a Marker for Polo-like Kinase 1 Activity In Vivo – Anticancer Research December 2010 vol. 30 no. 12 pp. 4973-4985

The Translational Control Tumor Protein (TCTP) Identified as Specific Marker for PLK1 Activity In-Vivo1


Correlation of Target Engagement and Treatment Response

0

2 0

4 0

6 0

8 0

1 0 0


% o

f le

uk

oc

yte

s

0 1 -0 0 2

0 7 -0 0 4

0 7 -0 1 0

1 5 8 15 22 1 5 8 15 22



Onvansertib + LDAC

01-002

0h 3h

D1 D5

0h

07-004 07-010

0h 3h

D1 D5

0h 0h 3h

D1 D5

0hpTCTP

TCTP

Onvansertib 12mg/m2 + LDAC

0

2 0

4 0

6 0

8 0

1 0 0


% o

f le

uk

oc

yte

s

0 7 -0 0 9

0 7 -0 1 1

1 5 8 15 22 1 5 8 15 22


0 7 -0 1 3

Onvansertib + Decitabine


07-01307-009

0h 3h

D1 D5

0h

07-011

0h 3h

D1 D5

0h 0h 3h

D1 D5

0h

Onvansertib 12mg/m2 + Decitabine

pTCTP

TCTP

pTCTP status as a surrogate for PLK1 inhibition

pTCTP status as a surrogate for PLK1 inhibition


Summary of Target Engagement and Correlation to Treatment Response

0 1 -0 0 2 0 7 -0 0 4 0 7 -0 1 0 0 7 -0 0 9 0 7 -0 1 1 0 7 -0 1 30 .0

0 .5

1 .0

1 .5

2 .0

pT

CT

P/T

CT

Pre

lati

ve

to

D

1 p

re d

os

e

D 1 p re d o s e (0 h )

D 1 p o s t d o s e (3 h )

D 5

Onvansertib 12mg/m2 + Cytarabine Onvansertib 12mg/m2 + Decitabine

0h 3hD1 D5

0hpTCTP

TCTP

0h 3hD1 D5

0h 0h 3hD1 D5

0h 0h 3hD1 D5

0h 0h 3h

D1 D5

0h 0h 3h

D1 D5

0h

Response% Blasts Response Response


Predictive Response Strategy

Patientreceives

single doseOnvansertib

AML PatientAssess target

engagement of PLK1 by Onvansertib

Pre-dose 3hr post-dose

0h 3h

D1 D5

0hpTCTP

TCTP

0h 3h

D1 D5

0h0h 3h

D1 D5

0hpTCTP

TCTP

0h 3h

D1 D5

0h

TargetEngagementEligible Patient

NO TargetEngagementNon-Eligible Patient

Evaluating Patient Responsiveness to Onvansertib1

0h 3hD1 D5

0hpTCTP

TCTP

1Trovagene Patent Pending – PLK1 Target Phosphorylation Status and Treatment of Cancer with PLK1 Inhibitors


Molecular Profiling and Patient Response in AML1

AML Genomic SubgroupFrequency of Patients Most Frequently Mutated Genes (%)

DNA Panel

RNA Panel

NPM1 mutation 27% NPM1(100), DNMT3A(54), FLT3(39), NRAS(19), TET2(16), PTPN11(15) X

Mutated chromatin, RNA-splicing genes, or both 18%

RUNX1(39), MLLPTD(25), SRSF2(22), DNMT3A(20), ASXL1(17), STAG2(16), NRAS(16),TET2(15),FLT3ITD(15)

X

TP53mutations, chromosomal aneuploidy, or both 13% Complex karyotope(68), -5/5q(47), -7/7q(44), TP53(44),

-17/17p(31), +8/8q(16) X X

inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11 5% inv(16) (100), NRAS(53), +8/8q(16), KIT(15),

FLT3TKD(15) X X

biallelic CEBPA mutations 4% CEBPAbiallelic(100), NRAS(30), WT1(21), GATA2(20) X

t(15;17)(q22;q12); PML-RARA 4% t(15;17) (100), FLT3 ITD(35), WT1(17) X X

t(8;21)(q22;q22); RUNX1-RUNX1T1 4% t(8;21) (100), KIT(38), -Y(33), -9q(18) X X

MLL fusion genes; t(x;11)(x;q23) 3% t(x;11q23) (100), NRAS(23) X X

inv(3)(q21q26.2) or t(3;3)(q21;q26.2); GATA2,MECOM(EVI1) 1% inv(3) (100), -7(85), KRAS(30), NRAS(30), PTPN11(30),

ETV6(15), PHF6(15), SF3B1(15) X X

IDH2R172 mutations and no other class-defining lesions 1% IDH2R172(100), DNMT3A(67), +8/8q(17) X

t(6;9)(p23;q34); DEK-NUP214 1% t(6;9) (100), FLT3ITD(80), KRAS(20) X X

1Papaemmanuil et al. Genomic classification and prognosis in acute myeloid leukemia; NEJM 2016;374:2209-2221


Genomic Profiling: Correlation of Mutation Detected in Blood and % Leukemic Cells

► Genomic analysis was performed on bone marrow and blood samples

► Mutations detected in bone marrow and blood were identical for all patients examined

► The mutation allelic frequencies detected in blood correlates with % of circulating leukemic cells

0

1 0

2 0

3 0

4 0

0

2 0

4 0

6 0

All

eli

c f

req

ue

nc

y (

%) %

of leu

ko

cytes

A S X L 1

S R S F 2

1 5 8 15 22

% L e u k e m ic c e lls

Mutations allelic frequencies and leukemic cells level in blood samples of patient 01-002

Patient Mutations detected

01-002ASXL1 c.1926_1927insG p.G646fs*12 SRSF2 c.284C>G p.P95R

07-004 TP53 c.955 A>T p.Lys319Ter

07-010

SRSF2 c.284C>G p.Pro95ArgRUNX1 c.511G>A p.Asp171AsnRUNX1 c.250A>C p.Thr84ProTET2 c.3633T>A p.Cys1211Ter

07-009

SF3B1 c.1998G>T p.Lys666Asn FLT3 c.250G>T p.Asp835Tyr RUNX1 c.984_985delAG p.Ala329fs GATA2 c.829A>G p.Ser277Gly

07-011 TP53 c.773A>C p.Glu258Ala

07-013PHF6 c.955C>T p.Arg319TerGATA2 c.962T>C p.Leu321Pro


Metastatic Castration-Resistant Prostate CancerOpportunity to Increase Duration of Response to Therapy

► 25,000 men die from metastatic prostate cancer annually and the five-year survival rate is 37%2

► Treatments – Zytiga® (Johnson & Johnson)/prednisone– Xtandi® (Astellas/Pfizer)

► Ongoing need to increase duration of response to treatment– Patients develop resistance within 9-15 months4 and do

not respond well to subsequent therapies

► Preclinical studies demonstrate synergy between Onvansertib and Zytiga®

– PLK1 inhibition improves abiraterone efficacy by repressing the androgen signaling pathway3,4

12017 Annual Report on Prostate Disease – Harvard Health Publications; 2GlobalData. Prostate Cancer—Global Drug Forecast and Market Analysis to 2023. Apr, 2015; 3 National Cancer Institute Metastatic cancer. Mar, 2013. Available at: http://www.cancer.gov/about-cancer/what-is-cancer/metastatic-fact-sheet; 4GAntonarakis, Emmannel – Current Understanding of Resistance to Abiraterone and Enzalutamide in Advanced Prostate Cancer; Clinical Advances in Hematology & Oncology – May 2016 – Volume 14, Issue 5

Prostate Cancer


PLK1 and Abiraterone Acetate (Zytiga®) Metastatic Castration-Resistant Prostate Cancer (mCRPC)

► All metastatic prostate cancer patients become castration-resistant

► PLK1 dependent microtubule dynamics promotes androgen receptor (AR) signaling1,2

► PLK1 inhibition improves abiraterone efficacy3

► Inhibition of PLK1 represses androgen signaling pathway4

► PLK1 inhibitors may add important therapeutic benefit for the treatment of castration-resistant prostate cancer patients5

1Xianzeng, Hou, Zhiguo, Li – PLK1-Dependent Microtubule Dynamics Promotes Androgen Receptor Signaling in Prostate Cancer; Prostate. 2013 September; 73(12): 1352–1363. doi:10.1002/pros.22683; 2 Arpaporn, Deeraksa, Jing, Pan - Plk1 is upregulated in androgen-insensitive prostate cancer cells and its inhibition leads to necroptosis; Oncogene. 2013 June 13; 32(24): 2973–2983. doi:10.1038/onc.2012.309; 3Clemens, Thoma – Prostate Cancer: PLK-1 Inhibition Improves Abiraterone Efficacy; Nature Reviews Urology volume11, page603 (2014); 4Zhang Z1, Chen L – Inhibition of PLK1 Represses Androgen Signaling Pathway in Castration-Resistant Prostate Cancer; Cell Cycle. 2015;14(13):2142-8. doi: 10.1080/15384101.2015.1041689; 5Klaus, Strebhardt - Drugging Plk1: An attractive approach to inhibit androgen receptor signaling; Cell Cycle. 2015 Jul 18; 14(14): 2193–2194


Ongoing Phase 2 Clinical Trial in mCRPC

Efficacy EndpointsEffect of Onvansertib in combination with Zytiga®/prednisone on disease control assessed by prostate-specific antigen (PSA) decline or stabilization pre- and post-treatment

Safety EndpointSafety of Onvansertib in combination with Zytiga®/prednisone

Exploratory EndpointTarget inhibition of PLK1, evaluation of relevant biomarkers and correlation with patient response and genomic profile

Onvansertib in Combination with Zytiga® and Prednisone in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Dosing Regimen

Onvansertib – 24 mg/m2

Days 1-5 (21-Day Cycle) + Zytiga®/prednisone daily

4 Cycles = 12 Weeks Disease Control based on PSA level

Duration Evaluation


Biomarker Strategy in mCRPC

PSA Assessment of Disease

Control

CTCsBaseline Genomic

Correlations with Response

TissueBaseline Tumor Profiling for

Predicting Synergy

PBMC’sAssess PLK1 Target

Inhibition

ctDNADynamic Changes

Associated with Treatment


PSA: NCCN Recommended Biomarker Trial Eligibility and Efficacy for mCRPC1

►PSA is a validated biomarker assessing disease stability or progression

►Prostate Cancer Clinical Trials Working Group (PCWG)1

has set criteria for the use of blood PSA levels:– Trial eligibility (defining progression) – Initial assessment of efficacy

1PCWG2: Sher et al, JCO, 2008, PCWG3: Sher et al, JCO, 2016


Biomarker Assessment Schedule

Onvansertib

abiraterone/ prednisone

Cycle 3 EOSCycle 2 Cycle 4

D1 D8 D15

PSA

CTCs

ctDNA

Cycle 1Week: 3 6 9 12

D1 D8 D1 D1 D1

5

pTCTP

Pre 1h

Baseline, Pre-dose/cycle 1 Pre-dose to cycle 2

Pre 1h

Pre-dose to cycle 3 Pre-dose to cycle 5

► Primary Endpoint: Proportion of patients achieving disease control after 12 weeks of study treatment, as defined by lack of PSA progression

Onvansertib Onvansertib Onvansertib


Colorectal Cancer: Unmet need in mCRC

► 140K new cases of CRC in 2018 with 64.5% 5 year survival1

– ~51K deaths per year from mCRC1

► Tumor biomarkers drive therapy decisions for 1st

line mCRC therapy2

– ~50% mCRC is RAS mutant (KRAS): FOLFOX/FOLFIRI/FOLFOXIRI

► Large unmet need in RAS mutant CRC2

– No targeted therapies are available for RAS mutant CRC

– 2nd line therapies have ~5% response rate in metastatic CRC (mCRC)

1https://seer.cancer.gov/statfacts/html/colorect.html; 2King et al, Frontline Strategies for Metastatic CRC, 2016, Amer J Hem/Onc; Loree&Kopetz, Recent Developments in treatment of mCRC, 2017, Ther Adv Med Onc;

Colorectal Cancer


Onvansertib in Pre-Clinical CRC Synergy with Irinotecan1

► In vitro:

– CRC cell lines are sensitive to Onvansertib:

25/27 cell lines tested had an IC50<1uM and 10 had an IC50<0.1uM

– Onvansertib is synergistic with paclitaxel, cisplatin, SN-38 and irinotecan

► In-vivo:

– Onvansertib inhibits tumor growth of CRC xenograft models3 independent models were tested and Onvansertibinduces maximal tumor regression of ~84% compared to vehicle

– The combination of Onvansertib with Irinotecan significantly reduces tumor growth compared with vehicle or either single agent treatment

Vehicle

Onvansertib 45 mg/kg

Onvansertib 60 mg/kg

rinotecan 45 mg/kg

Irinotecan (45 mg/kg) + Onvansertib (45 mg/kg)

1Data on File at Trovagene, Inc.


KRAS Mutation: Multiple in-vitro Studies Indicate Mutation is Biomarker for Onvansertib Sensitivity

► In a genome-wide RNAi screen there was found a synthetic lethal interactions (profound mitotic block/death) with KRAS oncogene and PLK1; Tested in 2 mutant & isogenic cell lines1

► KRAS-mutant cancer cell lines are more sensitive to PLK1 inhibition (BI2536)2

► KRAS mutated NIH3T3 cells showed higher sensitivity to onvansertib compare to KRAS wild-type (WT) cells3

1Luo J, Elledge SJ, Cell. 2009; 2Wang J., Liu M., Nat.Comm,2016; 3Investigator Brochure, Data-on-file, Trovagene

MutatedWild Type

Summary


Value Creating Milestones

Q4’18

Q1’19

Q2’19

Q3’19

Q4’19

ü AML – ASH Presentationü Efficacy and Safety Data Readouts (AML,

mCRPC)ü mCRC IND & Protocol Filed to FDA

ü AML – Reach MTD and RP2Dü Begin Enrolling AML Phase 2 trialü mCRPC – ASCO GU Presentationü Efficacy and Safety Data Readouts (AML

and mCRPC)ü Evaluate Expanding Clinical Program to

Europeü Formalize Japan Partnering

ü Initiate mCRC Phase 1b/2 Trialü Efficacy and Safety Data Readouts (AML,

mCRPC)ü AACR Presentation (AML, mCRPC)ü Complete Enrollment of AML Phase 2ü Complete Enrollment of mCRPC Phase 2 ü AML Companion Diagnostic

ü Efficacy and Safety Data Readouts (AML and mCRPC)

ü Assess Dose Escalation – Phase 1b mCRC Trial – Identify Phase 2 Dose

ü Begin Enrolling mCRC Phase 2

ü Data Readouts (AML, mCRPC, mCRC)

ü Begin Enrolling Phase 2 mCRC ü AML – ASH Presentation


Summary

► Precision Cancer Medicine, predictive biomarker approach

► Leveraging a proven cancer target, PLK1

► Onvansertib – first-in-class, 3rd generation, oral PLK1 inhibitor

► Synergy strategy – Onvansertib in combination with approved drugs

For additional information or questions please contact: [email protected]

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